The detection and treatment of cancerous tissue has been the subject of intense investigation for many years. One among the many approaches to its detection has concerned the identification of tumor specific antigens. Where these antigens can be identified, radionucleid labeled antibodies have been employed which tend to collect at tumor sites. When so concentrated, somewhat elaborate radiation detection equipment then is employed to record, for example, by imaging the concentrations of the emissive substances and thus to locate neoplastic tissue. Important advances in this procedure have been evidenced through the use of monoclonal antibodies or fragments thereof with a variety of radionucleides. Typical techniques for carrying out imaging of these antibodies have involved, for example, tomographic scanning, immunoscintigraphy and the like. The particular choice of radionucleid for labeling antibodies is dependent upon its nuclear properties, the physical half life, the detection instrument capabilities, the pharmacokinetics of the radiolabeled antibody, and the degree of difficulty of the labeling procedure. The most widely used of these radionucleides in nuclear medicine imaging include technetium, .sup.99m Tc, iodine .sup.125 I, .sup.131 I, and indium, .sup.111 In. Of the above, for localizing tumors of the gastro-intestinal tract, the radionucleid .sup.131 I is used as the marker of label in conjunction with imaging gamma cameras and the like which are relatively large and elaborate devices positioned above the patient during the imaging process.
In spite of its somewhat extensive utilization, .sup.131 I is not an ideal radionucleid for use in diagnostic medicine. The high energy gamma-photon emitted from .sup.131 I is poorly detected by the classic gamma camera and the like instrumentation. In addition, the administered marker emissions deliver a high radiation dose to the patient. Further, the imaging definition of these external imaging devices have not been satisfactory for many reasons. As tumor sites become smaller, the radionucleid concentrations thereat will tend to be lost, from an imaging standpoint, in the background or blood pool radiation necessarily present in the patient.
Over the recent past, a surgical procedure has been developed concerning the differentiation and removal of such neoplastic tissue through the use of much lower energy gamma emission levels for example, .sup.125 I (27-35 kev). While such a radiolabel cannot be employed with conventional external imaging or scanning devices, because the radiation is strongly absorbed by the tissue intermediate between the tumor and the surface of the patient's body, it has been found that when employed with a probe type detection structure, a highly effective differentiation technique can be evolved. More particularly, the longer half life of this type of radiolabel coupled with a surgical methodology involving the weighting of appropriate intervals from the time of introduction of the radiolabeled antibody to the patient to the time of surgery, can evolve a highly accurate differentiation of cancerous tumor. This improved method of localization, differentiation and removal of cancerous tumor involves a surgical procedure wherein the patient suspected of containing neoplastic tissue is administered an effective amount of a labeled antibody specific for neoplastic tissue and labeled with a radioactive isotope as above-noted exhibiting photon emissions of specific energy levels. Next, the surgical procedure is delayed for a time interval following such administration for permitting the labeled antibody to preferentially concentrate in any neoplastic tissue present in the patient and to be cleared from normal tissue so as to increase the ratio of photon emissions from the neoplastic tissue to the background photon emissions. Thereafter, an operative field of the patient is surgically accessed and tissue within the operative field to be examined for neoplastic tissue has the background photon emission count determined. Once the background photon emission count for the tissue within the operative field has been determined, a hand-held probe is manually positioned within the operative field adjacent tissue suspected of being neoplastic. This technique has been described as "radioimmuno guided surgery" (RIGS), a surgical approach developed by E. W. Martin, Jr., M.D., and M. O. Thurston, Ph.D. For additional information, achieved from probe counting for differentiation. Reference is made to the following technical publications:
______________________________________ I. "CEA-Directed Second-Look Surgery in the Asymptomatic Patient after Primary Resection of Colorectal Carcinoma", E. W. Martin, Jr., MD, J. P. Minton, MD, PhD, Larry C. Carey, MD. Annals of Surgery 202:1 (Sept. 1985 301-12. II. "Intraoperative Probe-Directed Im- munodetection Using a Monoclonal Antibody", P. J. O'Dwyer, MD, C. M. Mojzsik, RN MS, G. H. Hinkle, RPh, MS, M. Rousseau, J. Olsen, MD, S. E. Tuttle, MD, R. F. Barth, PhD, M. O. Thurston, PhD, D. P. McCabe, MD, W. B. Farrar, MD, E. W. Martin, Jr., MD. Archives of Surgery, 121 (Dec., 1986) 1321-1394. III. "Intraoperative Radioimmunodetection of Colorectal Tumors with a Hand-Held Radiation Detector", D. T. Martin, MD, G. H. Hinkle, MS RPh, S. Tuttle, MD, J. Olsen, MD, H. Abdel-Nabi, MD, D. Houchens, PhD, M. O. Thurston, PhD, E. W. Martin, Jr., MD. American Journal of Surgery, 150:6 (Dec., 1985) 672-75. IV. "Portable Gamma Probe for Radioimmune Localization of Experimental Colon Tumor Xenografts", D. R. Aitken, MD, M. O. Thurston, PhD, G. H. Hinkle, MS RPh, D. T. Martin, MD, D. E. Haagensen, Jr., MD, PhD, D. Houchens, PhD, S. E. Tuttle, MD, E. W. Martin, Jr., MD. Journal of Surgical Research, 36:5 (1984) 480-489. V. "Radioimmunoguided Surgery: Intra- operative Use of Monoclonal Antibody 17- 1A in Colorectal Cancer". E. W. Martin, Jr., MD, S. E. Tuttle, MD, M. Rousseau, C. M. Mojzisik, RN MS, P. J. O'Dwyer, MD, G. H. Hinkle, MS RPh, E. A. Miller, R. A. Goodwin, O. A. Oredipe, MA, R. F. Barth, MD, J. O. Olsen, MD, D. Houchens, PhD, S. D. Jewell, MS, D. M. Bucci, BS, D. Adams, Z. Steplewski, M. O. Thurston, PhD, Hybridoma, 5 Suppl 1 (1986) S97-108. ______________________________________
Reference further is made to commonly assigned application for U.S. Pat. Ser. No. 06/905,880 entitled "Method for Locating, Differentiating, and Removing Neoplasms" by Edward W. Martin, Jr., and Marlin O. Thurston, filed September 10, 1986, now U.S. Pat. No. 4,782,640, issued November 8, 1988.
The success of this highly effective differentiation and localization technique is predicted upon the availability of a probe-type detecting device capable of detecting extremely low amounts of radiation necessarily developed with the procedure. In this regard, low energy radionucleides are used such as .sup.125 I and the distribution of radiolabeled antibody with the nucleid is quite sparse so that background emissions can be minimized and the ratio of tumor-specific counts received to background counts can be maximized. Denen, et al., in application for U.S. Pat. Ser. No. 07/027,197, filed March 17, 1987, now U.S. Pat. No. 4,801,803, issued January 31, 1989, and assigned in common herewith describes a probe instrument and related control circuitry having the requisite sensitivity for use with such low energy radionucleides while retaining a robust structuring within a diminutive size suited for the rigorous surgical environment. This probe device is utilized currently under the trade designation "NEOPROBE" instrument.
Typically, the control consoles of radiation detectors such as Geiger counters and the like have functioned to carry out upper and lower energy threshold evaluations of detected impingement of radiation. In practice, each detected impingement is counted and is audibly manifested as a "click" sound. Some detector response circuitry stretches the duration of such abrupt output sounds to develop what may be referred to as a "beep". Similarly, solid-state counter components have been suggested in which, for example, a divide-by-ten function is carried out to adjust the frequency of an audible output from a radiation detector.
Experience in the surgical theater with the Neoprobe detection instrument has shown that the radiation encountered in the course of RIGS procedures is quite random. Where .sup.125 I is employed as a radiolabel or marker and variable intervals of time from marker injection into a patient to the time of surgery are encountered, background-to-tumor ratios may vary widely. These variances also are observed as the probe instrument is maneuvered from tissue region to tissue region in the course of a given surgery. As a consequence, where simple averaging of radiation impingements or "counts" over specified time intervals to derive count rates is employed, an unsatisfactory and somewhat distracting result obtains from an audible readout standpoint. Thus, a development of a relatively consistent system of audible cuing for the surgeon utilizing these probe instruments has been determined to be required. Such a system should avoid development of spurious audible outputs and provide outputs representing a signal treatment exhibiting consistency and reliability such that the surgeon is facilely guided to the situs of tumor.